Cancer is one of the major causes of hospitalization and death worldwide. Many of the therapies applied to cancer treatment are either ineffective or not well-tolerated by the patient. A promising approach that is little known but which has been successfully applied in Sweden, China, Germany, and Japan involves the electrical stimulation of a malignant tumor using direct current electricity. This has become known as electrochemical treatment (ECT). The clinical results have been obtained by applying electrical current via electrodes inserted percutaneously into the tumor. The treatment lasts for several hours during one or more sessions and can be used either alone or in conjunction with other therapy such as chemotherapy or radiation therapy. The therapy is well-tolerated in almost all patients.
This method is not to be confused with the electroporation technique which uses high voltages (xcx9c1 kV) with very short pulses.
The present invention overcomes some of the disadvantages of the ECT method mentioned above. It involves an implantable device consisting of a generator and one or more wires containing one or more electrodes. The electrodes are implanted in or near the tumor and the generator is implanted subcutaneously as close to the tumor as practical. The generator is powered either by an internal battery or via energy coupled to it from a source external to the body. The implantation is typically performed under local anesthesia and the device is left implanted for a period of months. Implantation permits electric current to be applied at lower levels for longer time periods, thus overcoming some of the drawbacks of the method above.
The nature of the implant results in some key differences from cardiac pacemaker design allowing for less stringent requirements on package and wire longevity. Other differences are manifested in the anchoring of the electrodes and in functions of the generator. The device complexity can range from very basic to sophisticated, including programmability of multiple parameters, patient alert mechanisms, sensors, and telemetry of information. The system may also include an external instrument for programming, telemetry reception, and data analysis. In one embodiment, chemotherapy drugs are infused from the generator in addition to the electrical stimulation.
Disease Prevalence
Cancer malignancies result in approximately 6,000,000 deaths worldwide each year. Of these, 538,000 were in the United States in 1995, representing over 23% of the total deaths in the United States. This number is up from 1970, when 331,000 deaths occurred. The estimated number of new cases in the United States in 1997 was 1,382,000. 40% of Americans will eventually be stricken with the disease and more than 1 in 5 will die from it. The percentage is increasing at about 1% per year and cancer deaths will soon outstrip deaths from heart disease. Much of the medical care cost from cancer results from hospitalization. In 1994 there were 1,226,000 hospital discharges in the United States related to cancer treatment.
The cost of cancer in terms of both human suffering and expenditures is staggering. Effective treatment methods which also result in fewer days of hospital care are desperately needed.
Cancer Treatment Methods
Primary treatment methods used in cancer therapy include surgery, radiation therapy, chemotherapy, hormone therapy and many others including bone marrow replacement, biological response modifiers, gene therapy, and diet. Therapy often consists of combinations of treatment methods. It is well known that these methods may result in sickness, pain, disfigurement, depression, spread of the cancer, and ineffectiveness. Despite recent announcements of potential pharmaceutical xe2x80x9ccures,xe2x80x9d these may work well in animals and in humans in certain cases, but researchers are cautious in overstating their effectiveness.
The therapy made possible by the novel devices described in this report is seen to have many benefits, including:
They may be used for either the primary treatment of neoplasms or during regression.
They require a single implant procedure, not repeated applications of invasive therapy, an important consideration in seriously ill individuals.
This and the lack of leads passing through the skin reduce the chance of infection.
Slow application of lower levels of current is preferable to larger quantities of charge over a short period of time. Extended use may prevent future metastases.
They have no disabling side effects as are found with chemotherapy or radiation therapy.
Their use is suitable in conjunction with other therapies.
Minimal hospital stays are required.
The device cost and complexity are low relative to pacemakers.
Since the therapy delivered by these implantable devices is based on the theory and clinical experience of B. E. Nordenstrom and others, their work and conclusions are first summarized below.
Early and Related Studies of Electrical Current in Tumors
Reis and Henninger caused regression of Jensen sarcomas in rats in 1951 using direct current and applied the technique to one patient with vulvar cancer. Lung tumors were first treated with direct current by Nordenstrom as reported in a 1978 publication. Experiments using small amounts of direct current to inhibit tumor growth were performed by Schanble et al. as well as others. Srinivasan et al. mention the possibility of controlling malignant tumor growth by direct current. Direct current has been used to coagulate blood in vessels leading to tumors and others (circa 1980) experimented with electrolytic destruction of tissue in animals using direct current (See Nordenstrom 1983). Mir et al. successfully treated tumors with Bleomycin and eight pulses of 100 microsecond width at 1 Hz with a field intensity of 1500 V/cm. They concluded that the minimum intensity required was 1100-1200 V/cm.
The Work of B. E. Nordenstrom
Bjorn Nordenstrom of Sweden, a pioneer and inventor in percutaneous needle biopsy and former Chairman of the Nobel Assembly, performed extensive research in electromedicine, developed a theory on the nature of bioelectricity and the healing process, and treated cancer in his patients as clinical proof of his theories. He called his model of biological control systems xe2x80x9cbiologically closed electric circuitsxe2x80x9d (BCEC) and sought to explain structural development in tissue injury and particularly around cancers. He found that treatment of cancer with DC electrodes changes the microenvironment of the cancer cells by electrophoresis of water and fat and electro-osmosis of water. The therapy that is based upon this principle is called xe2x80x9celectrochemical treatmentxe2x80x9d (ECT). Direct current ionizes tissue (as does ionizing radiation). Ionization of tissue via direct electrodes affects normal and malignant tissues differently. Low energy levels build up the therapeutic dose of energy from the inside of the tumor.
Tumor cells are more sensitive to changes in their microenvironment than are normal cells. The effect of the application of direct current to cells with platinum electrodes has been summarized succinctly by Li et al.:
Water migrates from the anode to the cathode while fat moves in the opposite direction (this migration causes local hydration around the cathode and dehydration around the anode).
The tissue becomes strongly acidic at the anode and strongly alkaline at the cathode.
The distributions of macro- and microelements in the tumor tissue are changed.
Protein is denatured in the electrochemical process (hemoglobin is transformed into acid hemming around the anode and alkaline hemming around the cathode).
Chlorine, which is a strong oxidant, is liberated at the anode, whereas hydrogen, which produced local cavitation in the tissue, is liberated at the cathode.
By means of DC delivering adequate electric charge, a series of biological and electrochemical reactions take place in tissue. The cell metabolism and its existing environment are severely disturbed. Both normal and tumor cells are destroyed rapidly and completely in this altered environment.
Berendson et al. believe that the toxic properties of the chlorine close to the anode and of the hydrogen chloride within a broader zone may be enough to explain the clinical effects of ECT and that the liberated hydrogen ions determine the extension of the locally destroyed zone around the anode. Several researchers have also observed that destruction occurs around both anode and cathode (Song et al., Matsushima et al., and Xin et al.) as well as within the electric field established between them. (In early works Nordenstrom cautions against making the center of the tumor the cathode as it will cause concentration of the acidity at the wrong location but later reports that, in some cases, better results were achieved with the cathode at the tumor.) Subsequent work in Asia found an advantage in locating both electrodes within the tumor (Xin, 1997). Nordenstrom believed that the electro-osmotic transport of water compresses capillaries and was seen to block large pulmonary arteries in dog experiments. He points out that a sufficiently long interval of vascular obstruction will seriously interfere with the living conditions of the tissues. Thus, primary tumor destruction is obtained, along with a change in surrounding conditions that prevent the tumor from living. ECT is also believed to enhance the immune system of the patient (Chen et al., Chou et al). In studies conducted in mice there was infiltration of lymphocytes in tumor tissue six days after treatment. Leukocytes have a negative surface charge and are known to be sensitive to low voltage changes and changes in pH and ion strength. At an electrode voltage as low as 100 mV leukocytes concentrated at the anode. Many leukocytes can be attracted to the anode at relatively low voltages but are massively destroyed in the anodic field at 10 V. Nordenstrom recognized that electrophoretic movements will take place at low voltages and current densities and he discussed possible tissue changes with, for example, 10V and 1 to 2 microamperes applied for 30 days. He wrote xe2x80x9c. . . it seems likely that DC treatment should be most beneficial when the technique approaches the mechanisms of closed circuit transport in spontaneous healing. This consideration implies the use of energies perhaps in the range of a few volts and a few microamperes over long time periods.xe2x80x9d He also deduced that AC potential may be used to heal tissue.
Procedurally, Nordenstrom used electrodes such as those shown in FIG. 1. The electrode is introduced through the chest wall (in the case of lung tumors) into the patient under guidance of biplane fluoroscopy or computed tomography under local anesthesia. In FIG. 1a hooked electrode ends 1 of platinum strings protruding from plastic tube 2 expand within tumor 3 to retain the electrode inside the tumor. In FIG. 1b platinum tubes 10-12 provide a larger surface area and can be chosen to correspond with the size of the tumor. Screw 14 is used to obtain biopsy tissue samples. The electrode 13 is shown implanted in tumor 20 in FIG. 1c. Tube 21 is constructed of Teflon(copyright). Alternatively, FIG. 1d shows a tapered platinum tube 30. Screw 31 is used to obtain tissue for biopsy. Area 32 consists of collapsed wings which, as shown in FIG. 1e, expand 40 to stabilize electrode 30 in the tumor. Nordenstrom recognized that a platinum electrode can be improved mechanically by adding iridium. He stated some guidelines for electrode design and implantation. The electrodes should present a large surface area but must be easily introducible without causing too much damage. He recognized in 1994 that regression of cancer can take place both around the anode and the cathode in the tumor. Placement of both electrodes within the tumor can lead to a treatment result comparable with an initially successful surgical removal of a cancer. However, as with surgical removal, metastases may later start growing in the tissue around the former tumor site. Positioning the anode and cathode far enough away from each other will create a distant field effect that should prevent future metastases. Thus, he believed that ECT of xe2x80x9csmall resectablexe2x80x9d cancers might be more efficient than conventional surgical resection. He advised that the use of multiple anodes and cathodes might cause an uneven distribution of current and recommended that electrodes be neither very close nor very far away from one another. The anode should be kept away from direct contact with large blood vessels if using the large currents and voltages used by Nordenstrom (but not with microampere level currents). The cathode may be placed in a blood vessel. Nordenstrom used a catheter that could be percutaneously inserted by Seldinger technique in, for example, a pulmonary artery. Electrodes can theoretically be placed on the skin (although he cautions against this in a later paper) or inserted through a chest wall, via a systemic artery, a systemic vein, a bronchus or in the pleural space. The venous routes and pleural space provide pathways for current that include the lymphatics. Nordenstrom also noted that flushing the anodal electrode with a charged agent such as Adriamycin or 5-fluoracil in a manner that causes even distribution of the drug with high concentration can lead to a remarkable regression and palliative effects of even large, incurable cancers. Whether supplied intravenously or orally, these two agents are attracted to the electrode, when given opposite polarity.
Nordenstrom reported treatment of 26 inoperable cancers of the lung in 20 patients starting in 1978 and followed up for 2 to 5 years. Twelve of the cancers were arrested and no fatalities occurred. He observed that in some cases multiple other small metastases in the lung parenchyma, distant from the sites of the electrodes, also appeared to regress after treatment of the larger metastases. He pointed out that the therapy was unoptimized at that time. Radiation treatment of lung tumors is not very effective. A rapid decrease in size of a poorly differentiated tumor after radiation treatment is often accompanied by re-growth of the tumor after a short time. Then the tumor is often more insensitive than previously to any attempts at a repeat course of radiation treatment. He foresaw an advantage of DC current treatment of primary neoplasms in the most surgically inaccessible locations such as the brain, spine, pancreas, liver and prostate and in patients who have been rejected for surgery, radiotherapy or chemotherapy because of poor general condition, cardiorespiratory insufficiency, diabetes mellitus, multiple locations of pulmonary metastases or failing response to chemotherapy. In a later report he cited favorable results with breast and bladder cancer. Also, he treated 14 patients with otherwise incurable cancers with ECT and a chemotherapeutic agent Adriamycin infused into the tumor. The principle, already mentioned above, is that an intramuscularly electropositive compound will be electrophoretically attracted to a neoplasm electrode given opposite polarity. This treatment was successful on larger tumors than was ECT alone and, in one case, abolished chronic cancer pain. Electrophoresis caused even distribution of the Adriamycin throughout the tumor, an effect probably not obtainable with injection.
Recent Human Results in Asia
B. E. Nordenstrom introduced electrochemical therapy in China in 1987 and, partly because of its relationship to traditional Chinese medicine (e.g., acupuncture), its use has been growing in China and interest has spread to Japan and Germany. Xin reported that, by 1994, 4081 malignant tumor cases were treated using ECT in 818 Chinese hospitals including esophageal, breast, skin, thyroid and liver cancers, as well as leg sarcomas. By the end of 1994 more than 6000 cases had been treated. Benign tumors such as heloid, angioma and freckle have also been treated.
Xin et al. published the results of treatment of 386 patients with lung cancer between 1987 and 1989. They found that damage of normal tissue could be eliminated by placing both electrodes into the tumor with anodes in the center and cathodes on the periphery. This has also enhanced the therapeutic effect significantly. They also concluded that the effect of ECT with lower current and longer treatment time is better than high current and shorter time.
Matsushima et al. and Chou et al also placed both electrodes inside the tumor. Matsushima et al studied 26 patients with 27 malignant tumors. The main complications were pain and fever for a few days after treatment. Pain during treatment, especially when the lesion was located in the neck or in soft tissue under the skin, was probably due to sensory nerve stimulation by the direct current. Some lung cancer patients had haemoptysis and pneumothorax.
Song et al. reported the treatment of tumors on the body surface with good results. ECT was found to be suitable for patients at great operative risk, for those who refuse surgery, for those who have not been cured by other means, and for those who have tumor recurrence. They discovered that metastatic enlarged lymph nodes can dissolve when the primary tumor is destroyed by ECT. The method was found to be simple, safe, effective, and readily accepted by patients. ECT can be used in primary as well as metastatic tumors, although the effect is better for primary tumors.
Lao et al. reported on the treatment of 50 cases of liver cancer using ECT. The indications for treatment were: the neoplasm was too large to be easily resected; it was unresectable because of location at the first or second hepatic portals; poor liver function secondary to severe cirrhosis making the patient unfit to stand the trauma caused by surgery; cancer infiltration of visceral organs such as the diaphragmatic muscle, peritoneum, or lymph nodes at the hepatic portals.
Quan discussed the ECT treatment of 144 cases of soft tissue and superficial malignant tumors. Short-term effectiveness of treatment was 94.5% for tumors with a diameter of less than 7 cm. and 29.4% for tumors with a diameter of more than 7 cm. He found that the earlier the stage the more effective the treatment and that ECT for malignant melanoma is more effective than chemotherapy and no different in results from surgery. However, ECT eliminated the need for amputation and dysfunction often caused by a too wide surgical excision.
Wang reported on ECT for 74 cases of liver cancer with tumors ranging from 3 to 20 cm. in diameter. The treatments of 3 to 5 hours were repeated 2 to 5 times with 7 to 10 days between each treatment. Total remission rate was 63.51%. Best results were obtained with tumor diameters less than 9 cm. Additional use of cytotoxic drugs and embolization resulted in a 87.5% cure rate.
Song et al. treated 46 patients having thyroid adenoma with ECT and reported a 97.8% cure rate with a single treatment. This represents successful treatment of benign tumors and destruction of precancerous and early malignant changes.
The above reports from China vary in the amount of technical detail presented regarding each study. In general, however, the electrodes were inserted under local anesthetic. The number of electrodes depended upon the tumor size and shape. The goal was to encompass the tumor with the electric field. Xin et al. state that, depending upon tumor composition and location, soft, flexible or hard electrodes with 0.1 cm diameters were used. The anode(s) was(were) placed within the tumor and the cathode(s) was(were) separated by from 1-3 cm. from the anode(s) or by a distance of 2-3 tumor diameters. There were a minimum of 2 electrodes and, at the other extreme, 2 anodes and 4-6 cathodes set up in two groups to establish two electric fields for a tumor of 6 cm. or larger. The treatment time varied from 1.5-5 hours and the number of sessions ranged from 1 to 5, again depending upon tumor size and response to therapy. The voltage used averaged about 8V but ranged from 6 to 15 V. The current ranged from 40-100 mA and the number of coulombs delivered per session ranged from 250 to 2000xc2x0 C. Quan gives a rule of thumb at 100xc2x0 C. per 1 cm of tumor diameter. Song observed that, at 100xc2x0 C., the area of destruction around the anode is 0.5-0.6 cm and the area around the cathode is 0.4-0.5 cm. Xin et al. observed some blockage of the heart beat in central lung cancer ECT with currents over 30 mA. Keeping the electrodes more than 3 cm from the heart corrected this effect.
The table below summarizes the types of tumors mentioned as having been treated by the researchers cited above:
Animal Results
Yokoyama et al. used direct current in canine malignant cancer tissue and found that cancer tissues of 2 cm. in diameter around the electrode became necrotic in 60 minutes. Bleomycin was then injected intravenously and was found to accumulate around the electrode in the majority of cases. Li et al. studied the mechanisms of ECT in normal dog liver and verified that the cell metabolism and its environment are destroyed in agreement with previous theory. Chen et al. studied ECT in mice and verified much of the theory, including the conclusions that tumor cells are more sensitive to changes of their microenvironment than are normal cells and that ECT stimulates the immune system, pointing out that, at an electrode voltage as low as 100 mV, leukocytes concentrate at the anode and lymphocyte anti-tumor response might be activated. Li et al., like Xin, placed both an anode and a cathode in the tumor. Chou et al. investigated ECT in mice and rats. Pointing out that constant voltage is used in clinics to prevent pain, they used a constant-voltage mode. They also cite the observations of Xin that untreated tumors sometimes disappear after ECT of the primary tumor. The hypothesis proposed to explain this was that the immune system was enhanced by ECT.
Electroporation
Another electrical therapy that has been attempted for the treatment of cancer is electroporation. This is based on the effective high voltage shocks which temporarily open pores in the cell membranes. This is normally considered a negative byproduct of shocks and is a negative side effect of, for example, defibrillation therapy. The application of a high voltage shock with fields on the order of hundreds of volts per centimeter will raise the transmembrane potential of the cell above 500 mV. This is over five times the normal activation potential swing of a cell and causes micro-pores to be temporarily open. If opened too long the pores are permanently damaged. The effect of this electroporation is a dramatic increase in the molecular exchange between the inside and outside of the cell.
Electroporation has primarily been used as a research tool and been evaluated for assistance in injecting various drugs, genetic material, proteins, and other substances into cells. Okino et al. used electroporation therapy and a cancer drug in an animal study.
Orlowski et al. also published another use of electroporation (he referred to it as electropermeabilization) of culture cells to increase the effectiveness of anti-cancer drugs. Belehradek et al. and Hofmann et al have both reported on the use of electroporation specifically to increase the efficacy of Bleomycin respectively in animals and humans.
There have been several patents discussing electrical treatment for cancer. These are primarily due to Nordenstrom as discussed here. All of these systems have been external instruments and there is no discussion or hint that the inventors here are aware of or conceived of a fully implantable or even a battery operated system.
Nordenstrom et al. patented an instrument for destroying a neoplasm in 1981. An instrument external to the body provides direct current and integrates it to determine charge. Electrodes are placed in the body, one in the neoplasm and one a distance away from it. The instrument controls the maximum voltage and current and can interrupt the current when the calculated charge reaches a predetermined value. In another patent granted to Nordenstrom in 1990 his concern was with a physiological way of healing, growing, or modifying tissue by applying a time-varying voltage. The voltage is a damped sine wave or a similar shape, each half cycle of the sine wave adjustably ranging from 0.1 to 10 days. The system can sense the direction of physiological healing and adjust the polarity of the voltage phase to complement it. In practice this is a system that appears to be used long-term but is not described as implantable except for the electrodes. The patent mentions the possibility of a rechargeable power source, programming of the controller, and automatic shutoff. D. Fontaine et al. patented a device reminiscent of an ablation device in 1996. It is of interest in that it includes a catheter tube containing electrodes as well as a lumen for the flow of electrolyte fluid to match the impedance of the tissue to the energy source. This is one example of catheters having electrodes as well as the ability to deliver fluids. B. Nordenstrom et al. patented another in 1986 for treatment of tumors. The patent discusses its advantages in positioning and retention of the electrode, in overcoming problems of gas formation and dehydration at the tumor, and the problem of material deposition on the electrode surface. The control instrument is specified as outside the body. Examples of fluids that can be delivered are cited as sodium chloride solution to increase the conductivity of the tumor as well as cell poison. Another patent to Nordenstrom in 1990 concerns a temporary electrode device suitable for the tumor destruction application. It was designed for ease of entry and removal and has an adjustable length electrode to adapt to different size tumors. P. Eggers et al. received a patent in 1997 for an instrument and a probe with two electrodes to sense whether tissue is normal or tumorous and, in the latter case, benign or malignant. Methods cited include measurement of impedance or dielectric constant. It also includes treatment of the tissue mass to effect necrosis, preferably via heat to cause cauterization. The device is specifically intended for use over a brief period of time.
There have been several patents dealing with the use of electroporation to inject substances into cells. For example Calvin teaches the use of electroporation to introduce DNA while Hofmann teaches several variations on this theme.
All of the patented art deals with either fully or largely external systems. This ranges from patches around the neck to external power sources into temporarily introduced needles and catheters. These all require use of a catheterization laboratory with all of the attendant costs and personnel, or could be conceivably used with a risk of infection with leads being left in the body and crossing the skin barrier.
With the possible exception of the painful high voltage shocks of electroporation therapy, it appears that the optimal electrocancer therapy obtains from long-term application of low voltages. This would seem to suggest that a battery operated implantable device would be optimal. However, this had not been taught in the literature. The closest are some semi-implantable systems such as an implantable RF Heater of Doss which has a coil inside the body which picks up a very high powered magnetic transmission and converts the heat. Similarly, Hofmann (U.S. Pat. No. 5,501,662) teaches a partially implanted system in which electrodes are left in a blood vessel to shock blood cells, receiving its power from an induction coil again from a high powered outside source. Neither of these is suitable for chronic care.
Thus, in spite of the evidence beginning to accumulate demonstrating the usefulness of some types of cancer electrical therapy, there has been no teaching by a practical implantable device. Such a device could cost effectively and safely deliver cancer therapy without the risk of infection from repeated introduction of needles and catheters into the body.
Also, the use of a system that would use all levels of electrical therapy for cancer treatment has not been taught even on an external basis.